Method of drying a material having a cohesive phase

ABSTRACT

A method for drying a material such as a polymer hydrogel which passes through a cohesive phase as it dries is disclosed. The method comprises agitating a composition while removing liquid until the solids content of the composition reaches a level at which the composition enters a cohesive phase, halting agitation, removing liquid from the composition in the absence of agitation, and resuming agitation. Practice of the present invention can eliminate the problems associated with adhesion of a material to itself and to process equipment during the cohesive phase.

RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Application No.60/269,327, filed on Feb. 16, 2001. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

BACKGROUND OF THE INVENTION

A substantial number of materials begin at or pass through a sticky, orcohesive, phase during drying operations. These materials can includefood products, polymers, pharmaceuticals and waste streams, amongothers. Polymer hydrogels are one class of materials that can experiencea cohesive phase during drying. Polymer hydrogels are characterized, inpart, by their ability to absorb water and retain it under pressure.Polymer hydrogels are widely used in the manufacture of personal hygieneproducts, but they also have important new pharmaceutical applications.

Many pharmaceutically important materials, such as polymer hydrogels,are initially produced with a higher moisture content than is found inthe end product. Accordingly, one of the final steps in the manufactureof such products can include drying the product to an acceptablemoisture level. Drying is usually necessary because it helps to minimizetransportation and packaging costs. Drying may also stabilize theproduct against microbial or chemical degradation. Such materials areusually dried in any of a number of commercially available dryers, whichtypically subject the material to continuous agitation as it dries. Theavailable dryers can vary in the method by which they reduce moistureand by the materials that they can process.

Many polymeric hydrogels experience a cohesive phase at certain levelsof moisture content. During this phase, polymer particles adhere withhigh affinity to each other and to equipment surfaces. This can makedrying polymer hydrogels particularly challenging. In dryers that usemechanical agitation, hydrogels in a cohesive phase can cause strainupon and damage to impellers, turbines, and end seal assemblies. Theincreased torque caused by agitating a material in its cohesive phasecan damage or stress the motors and drive systems used to agitate thematerial. The motors and gearboxes of such driers need to be suitablyrobust which is reflected in capital and operating costs.

Alternatively, attempts have been made to avoid a cohesive phase. Dryproduct can be back mixed to lower the moisture content of the dryerfeed below the threshold required for the cohesive phase. However,product back mixing can be undesirable in that the size of equipmentrequired is correspondingly increased. Further, product back-mixing isunsuitable for materials which are cohesive at very low moisture contentor for materials that are very wet at the beginning of the drying step.Product back-mixing may also be undesirable for the preparation ofmaterials that must meet exact production standards, such as materialsfor which loss of batch integrity is unacceptable.

Other methods to avoid a cohesive phase use additives to assist indrying, such as azeotrope-forming solvents or agents that affect thesurface wetting of the product. However, the use of additives andorganic solvents can be detrimental to pharmaceutical purity andgenerally increases production costs.

A need exists for an improved method to reduce the moisture content ofmaterials that experience a cohesive phase. Manufacturers need a processthat will permit processing of these materials without the highercapital, operating and maintenance expenses that can result frompracticing conventional drying techniques. Additionally, manymanufacturers, such as those in the pharmaceutical industry, need aprocess that does not use unnecessary additives or solvents andmaintains high purity standards.

SUMMARY OF THE INVENTION

This invention relates to a method for drying a material, such as apolymer hydrogel, that experiences a cohesive phase at certain levels oftemperature and moisture content. This invention is based, in part, onthe discovery that a material can be dried, in the absence of agitation,by applying a vacuum to the material as it passes through a cohesivephase. Thus, the invention allows for the suspension of agitation whilea composition passes through its cohesive phase.

The method of the present invention comprises agitating a compositioncomprising a solid and a liquid while removing the liquid until thesolids content of the composition reaches a level at which thecomposition enters a cohesive phase, halting agitation, removing liquidfrom the composition in the absence of agitation, and resumingagitation.

Consequently, practice of this invention can eliminate the problemsassociated with adhesion of the material to itself and to processequipment during the cohesive phase. Practice of the present inventioncan avoid the need for product back-mixing, for the use ofazeotrope-forming solvents, or for the adding of agents that effect thesurface wetting of the product. By avoiding these conventional dryingtechniques, the method of the present invention can help pharmaceuticalmanufacturers to maintain high purity standards and also to ensure batchintegrity. Additionally, since agitation is suspended during thecohesive phase, practice of the present invention can avoid stress,strain, and damage to dryers that use mechanical agitation.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE shows the linear relationship between moisture content andpolymer temperature during the cohesive phase of epichlorohydrincross-linked poly(allylamine hydrochloride).

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

This invention relates to a method for drying a material, such as apolymer hydrogel, that experiences a cohesive phase at certain levels oftemperature and moisture content. The method comprises agitating acomposition comprising solids and a liquid while removing the liquiduntil the solids content of the composition reaches a level at which thecomposition enters a cohesive phase, halting agitation, removing liquidfrom the composition in the absence of agitation, and resumingagitation. The method of the present invention allows the suspension ofagitation while a composition passes through its cohesive phase andthereby avoids the disadvantages associated with conventional dryingtechniques. Practice of the present invention can avoid the need forproduct back-mixing, for the use of azeotrope-forming solvents, or forthe adding of agents that effect the surface wetting of the product.Additionally, since agitation is suspended during the cohesive phase,practice of the present invention can avoid stress, strain, and damageto dryers that use mechanical agitation.

The terms “wet material” or “wet polymer” as used herein refer tocompositions that contain a substance that is not a solid at thetemperature of the composition. This substance may be, for example,water, an aqueous solution, or an organic solvent.

The term “loss on drying”, or “LOD”, refers to the weight fraction of acomposition that leaves that composition upon drying. Drying losses maybe attributable, for example, to water loss or to loss of volatileorganic substances.

Materials which undergo a cohesive phase as they dry include, forexample, polymer hydrogels, such as epichlorohydrin cross-linkedpoly(allylamine hydrochloride) described in U.S. Pat. Nos. 5,969,090 and5,900,475, incorporated by reference in their entirety, andwater-insoluble modified polyanionic polysaccharide compositionsdescribed in U.S. Pat. Nos. 4,937,270; 5,017,229; and 5,527,893,incorporated by reference in their entirety.

The term “cohesive phase” as used herein refers to a state in which acomposition is self-adhering. For instance, polymer particlesexperiencing this phase can adhere with high affinity to each other andto equipment surfaces. Polymer materials generally experience a cohesivephase at a given temperature during a particular range of moisturecontent. For example, epichlorohydrin cross-linked poly(allylaminehydrochloride) experiences a cohesive phase at various conditions ofmoisture and temperature, as is demonstrated in the Figure. The onset ofthe cohesive phase can be detected by fluctuations in the powerrequirements for agitating a composition. For instance, during thecohesive phase, the power required to agitate a composition cansignificantly increase.

The term “polymer hydrogel” as used herein refers to a polymericmaterial that is capable of retaining water near or within the structureof the material. The polymer material may be either a homopolymer or acopolymer. The polymers of the invention may or may not be cross-linkedwith a cross-linking agent.

A defining characteristic of a polymer hydrogel is the ability of thematerial to retain water, even under considerable pressure. Generally,the hydrogel is water swellable but is not substantially water soluble.The molecular weight of the final polymerized state; the chemicalcharacteristics of the constituent monomer groups, including the degreeof ionization of the salt form; and the chemical characteristics ofsubstituted groups on the polymer chain may all influence the ability ofthe polymer to retain water. Constituent monomer groups or substitutedgroups on the polymer chain influence the water holding capacity of thepolymer. The hydrophilic character of these structures can determine, atleast in part, the water retaining capacity of the polymer hydrogel.

The polymer hydrogels for use in the claimed invention can be organicpolymers. The polymers can include, for example, industrial polymers(e.g., for use in ion exchange), absorbent polymers (e.g., for use indisposable diapers), agrochemicals, or, preferably, pharmaceuticalpolymers.

The polymer hydrogel of the present invention is characterized by arepeating unit having the formula

or a copolymer thereof, wherein n is an integer and each R,independently, is H or a lower alkyl (e.g., having between 1 and 5carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl (e.g., phenyl)group; a repeating unit having the formula

or a copolymer thereof, wherein n is an integer, each R, independently,is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms,inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms,inclusive, such as ethylamino) or aryl (e.g., phenyl) group, and each X⁻is an exchangeable negatively charged counterion; a first repeating unithaving the formula

wherein n is an integer, each R, independently, is H or a lower alkyl(e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl), and each X⁻ is an exchangeablenegatively charged counterion; and a second repeating unit having theformula

wherein each n, independently, is an integer and each R, independently,is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms,inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms,inclusive, such as ethylamino) or aryl group (e.g., phenyl); a repeatingunit having the formula

or a copolymer thereof, wherein n is an integer, and R is H or a loweralkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl); a first repeating unit havingthe formula

wherein n is an integer, and R is H or a lower alkyl (e.g., havingbetween 1 and 5 carbon atoms, inclusive), alkylamino (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino) or arylgroup (e.g., phenyl); and a second repeating unit having the formula

wherein each n, independently, is an integer and R is H or a lower alkyl(e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl); a repeating group having theformula

or a copolymer thereof, wherein n is an integer, and each R₁ and R₂,independently, is H or a lower alkyl (e.g., having between 1 and 5carbon atoms, inclusive), and alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl group (e.g.,phenyl), and each X⁻ is an exchangeable negatively charged counterion,preferably, at least one of the R groups is a hydrogen group; a repeatunit having the formula

or a copolymer thereof, where n is an integer, each R₁ and R₂,independently, is H, an alkyl group containing 1 to 20 carbon atoms, analkylamino group (e.g., having between 1 and 5 carbons atoms, inclusive,such as ethylamino), or an aryl group containing 1 to 12 atoms (e.g.,phenyl); and a repeat unit having the formula

or a copolymer thereof, wherein n is an integer, each R₁, R₂ and R₃,independently, is H, an alkyl group containing 1 to 20 carbon atoms, analkylamino group (e.g., having between 1 and 5 carbons atoms, inclusive,such as ethylamino), or an aryl group containing 1 to 12 atoms (e.g.,phenyl), and each X⁻ is an exchangeable negatively charged counterion.

The negatively charged counterions may be organic ions, inorganic ions,or combination thereof. The inorganic ions suitable for use in thisinvention include the halides (especially chloride), phosphate,phosphite, carbonate, bicarbonate, sulfate, bisulfate, hydroxide,nitrate, persulfate, sulfite, and sulfide. Suitable organic ions includeacetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogencitrate, oxalate, succinate, tartrate, taurocholate, glycocholate, andcholate. The polymer salt is preferably the hydrogen chloride salt andcan include low salt or reduced salt forms of the polymer where, forexample, the salt is present in an amount between about 4% and 30% basedupon weight of polymer. Another example is sevelamer, which is storedand administered as a salt in which about 40% of the amine groups areprotonated as the hydrochloride salt (about 18% by weight of the polymeris chloride). Another example is poly(allylamine) wherein about 9.0% toabout 27.0% of the amine groups in the poly(allylamine) are protonated,such as poly(allylamine hydrochloride) where between about 4.0% andabout 12.0% of the polymer, by weight, is chloride anion.

Preferred polymer hydrogels have the structures set forth as describedabove. The polymers are preferably cross-linked, in some cases by addinga cross-linking agent to the reaction mixture during polymerization.Examples of suitable cross-linking agents are diacrylates anddimethacrylates (e.g., ethylene glycol diacrylate, propylene glycoldiacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate,propylene glycol dimethacrylate, butylene glycol dimethacrylate,polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate),methylene bisacrylamide, methylene bismethacrylamide, ethylenebisacrylamide, epichlorohydrin, toluene diisocyanate,ethylenebismethacrylamide, ethylidene bisacrylamide, divinyl benzene,bisphenol A dimethacrylate, bisphenol A diacrylate, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, acryloylchloride, or pyromellitic dianhydride. The amount of cross-linking agentis typically between about 0.5 and about 75 weight %, and preferablybetween about 1 and about 25% by weight, based upon combined weight ofcross-linking agent and monomer. In another embodiment, thecross-linking agent is present between about 2 and about 20% by weight.

In some cases the polymers are cross-linked after polymerization. Onemethod of obtaining such cross-linking involves reaction of the polymerwith difunctional crosslinkers, such as epichlorohydrin, succinyldichloride, the diglycidyl ether of bisphenol A, pyromelliticdianhydride, toluene diisocyanate, and ethylenediamine.

In particular, the invention is useful for cross-linked poly(allylaminehydrochloride). More preferred is epichlorohydrin cross-linkedpoly(allylamine hydrochloride). This polymer hydrogel is characterizedby a repeat unit having the formula

wherein a and b are the number of primary amine groups and a+b is about9, c is the number of cross-linking groups and c is about 1, n is thefraction of protonated amines and n is about 0.4, and m is an integer.The polymer is called sevelamer and is sold under the trademarkRenagel®. Another preferred polymer is colesevelam, sold under thetrademark Welchol™. The polymer is epichlorohydrin cross-linkedpoly(allylamine) alkylated with decylbromide and trimethylammoniumhexylbromide.

A substantial number of materials begin at or pass through a sticky, orcohesive, phase during drying operations. For example, it has beenobserved that cross-linked poly(allylamine hydrochloride) may enter acohesive phase during drying at particular temperatures and moistureconcentrations, for example such as at about 36 to 43° C. and about 80%solids content. During the cohesive phase the composition may becomeextremely rubbery and tough. Without being held to any particulartheory, it is believed that the cohesive phase experienced during dryingof cross-linked poly(allylamine hydrochloride) occurs as the polymerexperiences a polymer glass transition, i.e, the polymer transitionsfrom a rubbery to a glass state.

A polymer glass transition represents a phase transition wherein thepolymer changes from a rubbery, elastic material to a glassy, brittlematerial as the temperature of the material is reduced below the glasstransition temperature. At temperatures above the glass transition, amaterial tends to be soft and rubbery. As the temperature is decreased,the vibration amplitude of the polymer segments decrease causing thecomplex modulus of the polymer to increase exponentially. Upon furthercooling the material will enter the glass transition. As a materialpasses through the glass transition by continued cooling of the polymer,it will become hard and brittle and, subsequently, the complex moduluswill continue to rise until it reaches a glassy plateau.

Plasticizers generally work to reduce the modulus of a polymer at aparticular temperature by lowering the polymer's glass transitiontemperature. Generally, as the concentration of the plasticizer isincreased, the glass transition temperature of the composition occurs atprogressively lower temperatures. (Fried, Polymer Science andTechnology, Prentice Hall, N.J. 252-254 (1995)). This depression of thepolymer glass transition temperature is often linearly dependent uponplasticizer concentration. (Rodriguez, Principals of Polymer Systems,3^(rd) Ed., Hemisphere Publishing, NY 50-51 (1989)). The FIGURE showsthe linear relationship between moisture content and polymer temperatureduring the cohesive phase of epichlorohydrin cross-linkedpoly(allylamine hydrochloride). The Figure was produced by measuring theloss on drying (LOD) and polymer temperature of epichlorohydrincross-linked poly(allylamine hydrochloride), as it was dried in a MortonFM-130 Ploughshare Dryer, when the power required for agitation exceeded15 amps.

Without being held to any particular theory, it is believed that watercan act as a plasticizer for cross-linked poly(allylaminehydrochloride). During the early stages of drying it is believed thatthe temperature of cross-linked poly(allylamine hydrochloride) is wellabove its glass transition temperature. The Figure, however,demonstrates that epichlorohydrin cross-linked poly(allylaminehydrochloride) dried to a LOD of less than about 8% must pass through acohesive phase if drying temperatures are kept lower than 55° C. or ifthe product is discharged from the dryer at ambient temperatures. Thisinvention is based, in part, on the discovery that by removing liquid inthe absence of agitation from a composition of cross-linkedpoly(allylamine), the problems associated with drying during thecohesive phase can be avoided. It is believed that by removing liquid inthe absence of agitation, evaporative cooling reduces the temperature ofthe material below its glass transition temperature and, at the sametime, removal of plasticizing water increases the glass transitiontemperature of the composition.

This invention is also based, in part, on the discovery that byincreasing the temperature of a material prior to removing liquid in theabsence of agitation, the likelihood of passing the material through thecohesive phase is increased. By increasing its temperature, a materialcan be dried to a lower LOD before the glass transition is approached.Furthermore, increasing the drying temperature prior to suspendingagitation can allow greater moisture evaporation as the materialexperiences the cohesive phase.

In one aspect, the invention features a method of removing liquid from acomposition. The method comprises (a) agitating the composition whileremoving liquid until the composition enters a cohesive phase; (b)halting agitation; (c) removing liquid from the composition in theabsence of agitation until the composition passes through the cohesivephase; (d) resuming agitation; and (e) removing liquid from thecomposition while agitating the composition until the solids content ofthe composition reaches a pre-determined level. In one embodiment, thecomposition comprises a polymer. In another embodiment, the compositioncomprises a cross-linked polymer. Preferably, the composition comprisesa hydrogel. More preferably, the composition comprises an organicpolymer hydrogel used as an active pharmaceutical ingredient. Inparticular, the invention is useful for cross-linked poly(allylaminehydrochloride). Even more preferably, the composition comprisesepichlorohydrin cross-linked poly(allylamine hydrochloride).

In some embodiments, the composition is agitated at a pressure P1 priorto entering the cohesive phase, and the liquid is removed from thecomposition in the absence of agitation at a pressure P2, where P2 isless than P1. In various embodiments, either P2 or both P1 and P2 areless than atmospheric pressure. In one embodiment, P1 is about 25 to 500bar absolute. In another embodiment, P1 is about 80 to 480 mbarabsolute. In a preferred embodiment, P1 is about 50 to 200 mbarabsolute. Even more preferred, P1 is about 65 to 160 mbar absolute,e.g., P1 is about 110 to 140 mbar absolute. In one embodiment, P2 isless than about 100 mbar absolute. In a preferred embodiment, P2 is lessthan about 60 mbar absolute. Even more preferred, P2 is less than about13 mbar absolute.

In some embodiments, the composition is agitated at a temperature T1prior to entering the cohesive phase, and the liquid is removed from thecomposition in the absence of agitation at a temperature T2, where T2 isless than T1. In some embodiments, T1 is less than about 80° C., T1 isabout 30 to 80° C., or T1 is less than about 70° C. In a preferredembodiment, T1 is about 60 to 70° C. Preferably, the temperature of thecomposition is raised as high as possible, for example about 60 to 70°C., just before the material enters the cohesive phase. When a vacuum isapplied to the material, the temperature drops rapidly. The higher thetemperature just before the vacuum is applied, the more moisture will beremoved. Even more preferred, T1 is about 65° C. In one embodiment, T2is less than about 70° C. In a preferred embodiment, T2 is less thanabout 60° C., e.g., T2 is about 20 to 60° C.

In one aspect of the above mentioned method, agitation is resumed at apressure P3, wherein P3 is less than atmospheric pressure. In apreferred embodiment, P3 is about 50 to 200 mbar absolute. In anotheraspect, the composition is agitated at a pressure P1 prior to enteringthe cohesive phase, liquid is removed from the composition in theabsence of agitation at a pressure P2, and agitation is resumed atpressure P3, wherein P3 is substantially equal to P2. In one preferredembodiment, P2 and P3 are both less than atmospheric pressure, e.g.,less than about 60 mbar absolute. Alternatively, P2 may be substantiallyless than P3. In another one preferred embodiment, P1 and P3 are bothless than atmospheric pressure, e.g., about 50-200 mbar absolute.Alternatively, P3 may be substantially less than P1. In one embodiment,P1 is about 65 to 160 mbar absolute and P3 is less than about 80 mbarabsolute.

In one embodiment, the method comprises (a) agitating a composition at atemperature T1 while removing liquid until the composition enters acohesive phase, (b) halting the agitation, (c) removing liquid from thecomposition in the absence of agitation at a temperature T2 until thecomposition passes through the cohesive phase, (d) resuming agitation ata temperature T3, and (e) removing liquid from the composition whileagitating the composition at a temperature T3 until the solids contentof the composition reaches a pre-determined level, where T3 is less thanT1. In a preferred embodiment, T1 is about 30 to 80° C. More preferred,T1 is about 60 to 70° C. In one embodiment, T3 is less than the glasstransition temperature of the polymer composition at a given moisturecontent. In a preferred embodiment, T3 is about 30 to 60° C.

In another preferred embodiment the method comprises (a) agitating acomposition at a temperature T1 while removing liquid until thecomposition enters a cohesive phase, (b) halting the agitation, (c)removing liquid from the composition in the absence of agitation at atemperature T2 until the composition passes through the cohesive phase,(d) resuming agitation at a temperature T3, and (e) removing liquid fromthe composition while agitating the composition at a temperature T3until the solids content of the composition reaches a pre-determinedlevel, where T3 is greater than T2.

Liquid can be removed from the composition in the absence of agitationuntil the composition is no longer in the cohesive phase. In oneembodiment, liquid is removed from the composition in the absence ofagitation for at least about 30 minutes. Preferably, liquid is removedfrom the composition in the absence of agitation for at least about onehour.

In another aspect, the invention relates to a method of removing liquidfrom a composition that comprises a cross-linked poly(allylamine). Themethod comprises (a) agitating the composition at a pressure, P1, about65 to 160 mbar absolute and at a temperature, T1, about 60 to 70° C.while removing liquid until the composition enters a cohesive phase; (b)halting agitation; (c) removing liquid from the composition at apressure, P2, less than about 60 mbar absolute and at a temperature, T2,less than about 60° C. in the absence of agitation for at least 30minutes; (d) resuming agitation once the composition has passed throughthe cohesive phase; and (e) removing liquid from the composition whileagitating the composition until the solids content of the compositionreaches a pre-determined level.

In a preferred embodiment, the composition comprises a cross-linkedpolymer that is epichlorohydrin cross-linked poly(allylaminehydrochloride).

In a preferred embodiment, P1 is about 110 to 140 mbar absolute. Inanother preferred embodiment, T1 is about 65° C. In yet anotherpreferred embodiment, liquid is removed from the composition in theabsence of agitation for at least about one hour.

Generally, an apparatus suitable for drying a material that experiencesa cohesive phase is a vessel with means for agitating the material,means for controlling the temperature of the contents of the vessel,and, optionally, means for controlling the pressure of the vessel. Forexample, a commercially available rotary vacuum dryer can be used to drya material having a cohesive phase. Rotary vacuum dryers suitable forpracticing the invention can include stationary shell, rotating shell,and rotating double-cone vacuum dryers. One example of a suitable dryerunit is a Morton FM-130 Ploughshare Dryer (Morton Machines Company Ltd.,Motherwell, Scotland). Other suitable dryers can include spray dryers,calciners, microwave dryers, and fluidized beds. Measurement and controlof temperature, pressure, agitation rate, and agitator power draw can beautomated and integrated, e.g., through a process control system.

In one embodiment, upon being placed into a dryer, a wet material isagitated at a temperature T1 and pressure P1. The material may be driedby controlling either the pressure or the temperature of the dryer; ifone of the pressure or temperature is set, the other is necessarilydetermined for a dryer of a given volume. In one embodiment, P1 is aboutatmospheric pressure or less than atmospheric pressure, for exampleabout 25 to 500 mbar absolute. In another, P1 is about 80 to 480 mbarabsolute. In a preferred embodiment, P1 is about 50 to 200 mbarabsolute. Even more preferred, P1 is about 65 to 160 mbar absolute. Insome embodiments, T1 is less than about 80° C., T1 is about 30 to 80°C., or T1 is less than about 70° C. In a preferred embodiment, T1 isabout 60 to 70° C. Even more preferred, T1 is about 65° C.

As moisture is removed from the composition and the composition beginsto approach its cohesive phase, fluctuations will be noted in the powerdraw of the agitator unit in the dryer, as the temperature, pressure,and humidity of the system change. For example, as the materialapproaches the cohesive phase, the humidity of the outlet air can drop,and the temperature of the air can rise. Just prior to the materialentering the cohesive phase, it is preferred to raise the temperature ofthe composition to about 60 to 70° C., e.g., T1 is about 65° C. As soonas this temperature range is reached or agitator power draw increasessubstantially, agitation is halted. In a preferred embodiment, a vacuumis applied to the dryer. Preferably, the pressure in the dryer isreduced to less than about 100 mbar absolute. Even more preferably, thepressure of the dryer is reduced to less than about 60 mbar absolute,e.g., the pressure in the dryer is reduced to less than about 13 mbarabsolute. Once a vacuum is applied, the dryer and material temperaturesdrop rapidly.

In a preferred aspect of the invention, the differential between thetemperature during agitation and the temperature when agitation stops isas great as possible to encourage moisture evaporation. Preferably, thetemperature of the composition is raised as high as possible, forexample about 60 to 70° C., just before the material enters the cohesivephase. When a vacuum is applied to the material, the temperature dropsrapidly. The higher the temperature just before the vacuum is applied,the more moisture will be removed.

In a preferred embodiment, liquid is removed from the composition in theabsence of agitation at a temperature T2 and pressure P2, which arelower than the initial drying temperature T1 and pressure P1. During thecohesive phase the material can remain stationary under full vacuum, ornearly full vacuum, while moisture is removed by way of the vacuummechanism. While the product is stationary under reduced pressure,evaporative cooling considerably reduces the product temperature andmoisture. During this stage, moisture is removed from the interior ofthe material. In one embodiment, P2 is less than about 100 mbarabsolute. In a preferred embodiment, P2 is less than about 60 mbarabsolute, e.g., P2 is less than about 13 mbar absolute. In oneembodiment, T2 is less than about 70° C. In a preferred embodiment, T2is less than about 60° C., e.g., T2 is about 20 to 60° C. In oneembodiment, liquid is removed from the composition in the absence ofagitation for a period of at least about 30 minutes. In a preferredembodiment, liquid is removed from the composition in the absence ofagitation for a period of at least about one hour.

Once the cohesive phase has passed, agitation may be resumed and dryingmay be continued to obtain a composition having the desired level ofmoisture. In one embodiment, the composition is dried under vacuum,e.g., for about 30 minutes to 4 hours.

In an alternative embodiment, two dryers may be used in series. The useof two dryers in series can be desirable for high throughputapplications. The first, or primary, dryer can be used to remove excessmoisture quickly from material that is not yet at the cohesive phase.Then the second dryer can dry the material as it approaches the cohesivephase and as it passes through the cohesive phase. Both dryers can havemeans for agitating the material to be dried and also means for alteringthe pressure in the drying vessel.

The wet material in the primary dryer is dried at temperature T1 andpressure P1. Just prior to the onset of the cohesive phase the materialis transferred to a secondary dryer. Material transferred into thesecondary dryer is, upon entry of its cohesive phase, subjected totemperature T2 and pressure P2, wherein T2 and P2 are less than T1 andP1, respectively. Agitation, if applied, is suspended while the materialis in the cohesive phase. Once the cohesive phase has passed, agitationcan be resumed.

In one embodiment, the primary dryer is a spray dryer. In such a dryer,the composition enters through the top of the dryer. As the materialenters the dryer, it is atomized. As the particles fall through thedryer, the moisture on the exterior of the particles evaporates. In thisfirst dryer, the material is subjected to very high heat, e.g., thetemperature of the dryer can be as high as about 100 to 600° C.Preferably, the temperature of the material only reaches about 50 to 60°C., though, as a result of evaporative cooling. The material remains insuch a primary dryer for a very short time period, e.g., about 10seconds.

The material then exits the primary dryer and enters the secondarydryer. For example, the material can fall out of the bottom of the firstdryer, into the second dryer, which can be, for example, a fluid beddryer. In the fluid bed dryer, the material can reach the temperature ofthe dryer, so the temperature of the dryer should not exceed about 20 to60° C. The particles in a fluid bed dryer are suspended in a stream ofair. The particles start out as a suspension, but as the particlesapproach the cohesive phase, they begin to agglomerate and drop to astationary surface of the dryer.

Alternatively, a single dryer with two different drying stages can beused. The first stage can be used to dry the material before it entersthe cohesive phase, and the second stage can be used to dry to materialas is approaches and passes through the cohesive phase. Each of thedryer stages can have means for agitating the material to be dried aswell as means for altering the pressure in the drying vessel of therespective stage.

In one embodiment, a composition is dried in a first dryer stage at atemperature T1 and a pressure P1. As the cohesive phase of the materialapproaches, the material is transferred using a means for conveyancesuch as, for example, a conveyor belt, to the second dryer stage. There,in the second stage, the material is dried at temperature T2 andpressure P2, where T2 is less than T1 and P2 is less than P1.

The invention will be further described in the following example, whichdoes not limit the scope of the invention described in the claims.

EXAMPLE

A wet epichlorohydrin crosslinked poly(allylamine hydrochloride) gelhaving mass of 27.2 kg and a solids content of 42.3% was fed into aMorton FM-130 Ploughshare Dryer. The moisture in the gel was an aqueous70% (v/v) isopropanol solution. Drying was initiated by starting themain drive agitator and pulling a vacuum. The mixing speed was set at 80RPM, and the heating jacket temperature was set at 80° C. The vacuumduring drying was adjusted to 38-60 Torr by opening an air bleed valveinto the vacuum pump.

Drying was allowed to continue under the above conditions until theonset of the cohesive phase. As the cohesive phase approached, theproduct temperature and vacuum level in the dryer steadily rose, andpower draw fluctuations in the main drive steadily increased. Once thepower draw fluctuations exceeded 14 amps on the main drive shaft,agitation was stopped, and the air bleed into the vacuum pump was shutoff. The solids content of the product at this time was 90.5%. Theproduct was allowed to sit in the dryer under full vacuum forapproximately 30 minutes. After 30 minutes, agitation was restarted andno power draw fluctuations were detected. The solids content of theproduct at this time was 93.7%. Drying continued under full vacuum foran additional 25 minutes, after which time the product was dischargedfrom the dryer.

Other Embodiments

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method of removing liquid from a composition,the method comprising: (a) agitating the composition while removingliquid until the composition enters a cohesive phase; (b) haltingagitation; (c) removing liquid from the composition in the absence ofagitation until the composition passes through the cohesive phase; (d)resuming agitation; and (e) removing liquid from the composition whileagitating the composition until the solids content of the compositionreaches a pre-determined level.
 2. The method of claim 1 wherein thecomposition is agitated at a pressure P1 and the liquid is removed fromthe composition in the absence of agitation at a pressure P2, wherein P2is less than P1.
 3. The method of claim 2 wherein P2 is less thanatmospheric pressure.
 4. The method of claim 3 wherein P2 is less thanabout 60 mbar absolute.
 5. The method of claim 4 wherein P2 is less thanabout 13 mbar absolute.
 6. The method of claim 2 wherein P1 is less thanatmospheric pressure.
 7. The method of claim 6 wherein P1 is about 80 to480 mbar absolute.
 8. The method of claim 6 wherein P1 is about 65 to160 mbar absolute.
 9. The method of claim 1 wherein the composition isagitated at a temperature T1 and the liquid is removed from thecomposition in the absence of agitation at a temperature T2, wherein T2is less than T1.
 10. The method of claim 9 wherein T1 is about 30 to 80°C.
 11. The method of claim 10 wherein T1 is about 60 to 70° C.
 12. Themethod of claim 9 wherein T2 is less than about 60° C.
 13. The method ofclaim 12 wherein T2 is about 20 to 60° C.
 14. The method of claim 1wherein agitation is resumed at pressure P3, wherein P3 is less thanatmospheric pressure.
 15. The method of claim 14 wherein P3 is about 50to 200 mbar absolute.
 16. The method of claim 1 wherein the compositionis agitated at a pressure P1 prior to entering the cohesive phase, theliquid is removed from the composition in the absence of agitation at apressure P2, and agitation is resumed at pressure P3, wherein P3 issubstantially equal to P2.
 17. The method of claim 16 wherein P2 and P3are each less than about 60 mbar absolute.
 18. The method of claim 1wherein the composition is agitated at a pressure P1 prior to enteringthe cohesive phase, the liquid is removed from the composition in theabsence of agitation at a pressure P2, and agitation is resumed atpressure P3, wherein P3 is substantially equal to P1.
 19. The method ofclaim 18 wherein P1 and P3 are each about 50 to 200 mbar absolute. 20.The method of claim 1 wherein the composition is agitated at atemperature T1, the liquid is removed from the composition in theabsence of agitation at a temperature T2, and agitation is resumed at atemperature T3 after the composition passes through the cohesive phase,wherein T3 is less than T1.
 21. The method of claim 20 wherein T3 isabout 30 to 60° C.
 22. The method of claim 20 wherein T1 is about 60 to70° C.
 23. The method of claim 1 wherein the composition is agitated ata temperature T1, the liquid is removed from the composition in theabsence of agitation at a temperature T2, and agitation is resumed at atemperature T3 after the composition passes through the cohesive phase,wherein T3 is greater than T2.
 24. The method of claim 1 wherein thecomposition comprises a polymer.
 25. The method of claim 24 wherein thepolymer comprises a cross-linked polymer.
 26. The method of claim 1wherein the composition comprises a hydrogel.
 27. The method of claim 26wherein the hydrogel comprises an organic polymer hydrogel used as anactive pharmaceutical ingredient.
 28. The method of claim 27 wherein thepolymer hydrogel comprises a cross-linked poly(allylamine).
 29. Themethod of claim 28 wherein the cross-linked poly(allylamine) comprisesepichlorohydrin crosslinked poly(allylamine hydrochloride).
 30. Themethod of claim 1 wherein the liquid is removed from the composition inthe absence of agitation for at least about 30 minutes.
 31. The methodof claim 30 wherein the liquid is removed from the composition in theabsence of agitation for at least about one hour.
 32. A method ofremoving liquid from a composition comprising a cross-linkedpoly(allylamine), the method comprising: (a) agitating the compositionat a pressure, P1, about 65 to 160 mbar absolute and at a temperature,T1, about 60 to 70° C. while removing liquid until the compositionenters a cohesive phase; (b) halting agitation; (c) removing liquid fromthe composition at a pressure, P2, less than about 60 mbar absolute andat a temperature, T2, less than about 60° C. in the absence ofagitation; (d) resuming agitation once the composition has passedthrough the cohesive phase; and (e) removing liquid from the compositionwhile agitating the composition until the solids content of thecomposition reaches a pre-determined level; wherein the liquid isremoved from the composition in the absence of agitation for at least 30minutes.
 33. The method of claim 32 wherein the cross-linkedpoly(allylamine) comprises epichlorohydrin cross-linked poly(allylaminehydrochloride).
 34. The method of claim 32 wherein P1 is about 110 to140 mbar absolute.
 35. The method of claim 32 wherein T1 is about 65° C.36. The method of claim 32 wherein the liquid is removed from thecomposition in the absence of agitation for at least one hour.